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Nerve injury can induce aberrant changes in the spine; these changes are due to, or at least partly governed by, transcription factors that contribute to the genesis of neuropathic allodynia. Here, we showed that spinal nerve ligation (SNL, a clinical neuropathic allodynia model) increased the expression of the transcription factor Tbx5 in the injured dorsal horn in male Sprague Dawley rats. In contrast, blocking this upregulation alleviated SNL-induced mechanical allodynia, and there was no apparent effect on locomotor function. Moreover, SNL-induced Tbx5 upregulation promoted the recruitment and interaction of GATA4 and Brd4 by enhancing its binding activity to H3K9Ac, which was enriched at the Trpv1 promotor, leading to an increase in TRPV1 transcription and the development of neuropathic allodynia. In addition, nerve injury-induced expression of Fbxo3, which abates Fbxl2-dependent Tbx5 ubiquitination, promoted the subsequent Tbx5-dependent epigenetic modification of TRPV1 expression during SNL-induced neuropathic allodynia. Collectively, our findings indicated that spinal Tbx5-dependent TRPV1 transcription signaling contributes to the development of neuropathic allodynia via Fbxo3-dependent Fbxl2 ubiquitination and degradation. Thus, we propose a potential medical treatment strategy for neuropathic allodynia by targeting Tbx5.Significance Statement Nerve injury-induced epigenetic changes in Tbx5 enhance TRPV1 expression in the dorsal horn, with Tbx5 recruiting GATA4 and Brd4 for epigenetic modification of TRPV1. The Fbxo3-mediated Fbxl2 ubiquitination pathway stabilizes Tbx5, increasing its transcriptional activity and enhancing TRPV1 expression, contributing to the initiation and maintenance of neuropathic pain via epigenetic reprogramming.
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A synthetically useful approach to functionalized triazoles is described via the reaction of ß-carbonyl phosphonates and azides. 1,4- and 1,5-disubstituted and 1,4,5-trisubstituted triazoles can be regio- and chemoselectively accessed under mild conditions in good to excellent yields (31 examples, up to 99%). A mechanism is proposed that rationalizes the avoidance of the 4-phosphonate byproducts, which is aligned with crystallographic and experimental evidence.
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Z-discs are core ultrastructural organizers of cardiomyocytes that modulate many facets of cardiac pathogenesis. Yet a comprehensive proteomic atlas of Z-disc-associated components remain incomplete. Here, we established an adeno-associated virus (AAV)-delivered, cardiomyocyte-specific, proximity-labeling approach to characterize the Z-disc proteome in vivo. We found palmdelphin (PALMD) as a novel Z-disc-associated protein in both adult murine cardiomyocytes and human pluripotent stem cell-derived cardiomyocytes. Germline and cardiomyocyte-specific Palmd knockout mice were grossly normal at baseline but exhibited compromised cardiac hypertrophy and aggravated cardiac injury upon long-term isoproterenol treatment. By contrast, cardiomyocyte-specific PALMD overexpression was sufficient to mitigate isoproterenol-induced cardiac injury. PALMD ablation perturbed the transverse tubule (T-tubule)-sarcoplasmic reticulum (SR) ultrastructures, which formed the Z-disc-associated junctional membrane complex (JMC) essential for calcium handling and cardiac function. These phenotypes were associated with the reduction of nexilin (NEXN), a crucial Z-disc-associated protein that is essential for both Z-disc and JMC structures and functions. PALMD interacted with NEXN and enhanced its protein stability while the Nexn mRNA level was not affected. AAV-based NEXN addback rescued the exacerbated cardiac injury in isoproterenol-treated PALMD-depleted mice. Together, this study discovered PALMD as a potential target for myocardial protection and highlighted in vivo proximity proteomics as a powerful approach to nominate novel players regulating cardiac pathogenesis.
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BACKGROUND: Paclitaxel (PTX), which is a first-line chemotherapy drug used to treat various types of cancers, exhibits peripheral neuropathy as a common side effect that is difficult to treat. Protein arginine methyltransferase 5 (PRMT 5) is a key regulator of the chemotherapy response, as chemotherapy drugs induce PRMT5 expression. However, little is known about the PRMT5-mediated epigenetic mechanisms involved in PTX-induced neuropathic allodynia. METHODS: Sprague-Dawley rats were intraperitoneally given PTX to induce neuropathic pain. Biochemical analyses were conducted to measure the protein expression levels in the dorsal root ganglion (DRG) of the animals. The von Frey test and hot plate test were used to evaluate nociceptive behaviors. RESULTS: PTX increased the PRMT5 (mean difference [MD]: 0.68, 95% confidence interval [CI], 0.88-0.48; P < .001 for vehicle)-mediated deposition of histone H3R2 dimethyl symmetric (H3R2me2s) at the transient receptor potential vanilloid 1 ( Trpv1 ) promoter in the DRG. PRMT5-induced H3R2me2s recruited WD repeat domain 5 (WDR5) to increase trimethylation of lysine 4 on histone H3 (H3K4me3) at Trpv1 promoters, thus resulting in TRPV1 transcriptional activation (MD: 0.65, 95% CI, 0.82-0.49; P < .001 for vehicle) in DRG in PTX-induced neuropathic pain. Moreover, PTX increased the activity of NADPH oxidase 4 (NOX4) (MD: 0.66, 95% CI, 0.81-0.51; P < .001 for vehicle), PRMT5-induced H3R2me2s, and WDR5-mediated H3K4me3 in the DRG in PTX-induced neuropathic pain. Pharmacological antagonism and the selective knockdown of PRMT5 in DRG neurons completely blocked PRMT5-mediated H3R2me2s, WDR5-mediated H3K4me3, or TRPV1 expression and neuropathic pain development after PTX injection. Remarkably, NOX4 inhibition not only attenuated allodynia behavior and reversed the above-mentioned signaling but also reversed NOX4 upregulation via PTX. CONCLUSIONS: Thus, the NOX4/PRMT5-associated epigenetic mechanism in DRG has a dominant function in the transcriptional activation of TRPV1 in PTX-induced neuropathic pain.
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Antineoplásicos , Neuralgia , Ratos , Animais , Paclitaxel/toxicidade , Paclitaxel/metabolismo , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteína-Arginina N-Metiltransferases/farmacologia , Ratos Sprague-Dawley , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Hiperalgesia/metabolismo , Gânglios Espinais , Canais de Cátion TRPV/genética , Antineoplásicos/efeitos adversos , Neuralgia/induzido quimicamente , Neuralgia/genética , Neuralgia/metabolismo , Epigênese GenéticaRESUMO
The Sodium-glucose co-transporter 2 (SGLT2) inhibitor is an anti-glycemic agent that frequently used in type 2 diabetes mellitus (T2DM) with antioxidant effects. Endometrial cancer (EC) is a common gynecological malignancy that correlates with oxidative stress. The aim in the present study is to survey the potential association between the SGLT2 inhibitor administration and the incidence of EC by the application of the National Health Insurance Research Database (NHIRD) of Taiwan. A retrospective cohort study was directed and the T2DM participants were divided into the SGLT2 inhibitors users and non-SGLT2 inhibitors users. After matching, a total of 163,668 and 327,336 participants were included into the SGLT2 inhibitors and control groups, respectively. The primary outcome is regarded as the development of EC according to the diagnostic, image, and procedure codes. Cox proportional hazard regression was employed to generate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) of EC between the two groups. There were 422 and 876 EC events observed in the SGLT2 inhibitors and control groups, respectively. The SGLT2 inhibitors group demonstrated a significantly lower incidence of EC formation compared to the control groups (aHR: 0.87, 95% CI: 0.76-0.99). In the subgroup analysis, the correlation between SGLT2 inhibitor administration and lower rate of EC existed in the T2DM individuals with aged under 60. Moreover, the association between SGLT2 inhibitor administration and lower EC incidence only presented in the T2DM population with SGLT2 inhibitor administration under one year (aHR: 0.58, 95% CI: 0.45-0.73). In conclusion, the administration of SGLT2 inhibitors correlates to lower incidence of EC in T2DM population.
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Diabetes Mellitus Tipo 2 , Neoplasias do Endométrio , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Feminino , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Neoplasias do Endométrio/epidemiologia , Pessoa de Meia-Idade , Incidência , Taiwan/epidemiologia , Estudos Retrospectivos , Idoso , AdultoRESUMO
Background: The glucagon-like peptide 1 receptor agonist (GLP-1RA) is an antidiabetic medication with vascular protection and anti-inflammatory properties. Theoretically, the use of GLP-1RA should inhibit the development of open-angle glaucoma (OAG) as both vascular damage and inflammation are associated with OAG. Therefore, our objective was to investigate the association between the application of GLP-1RA and the subsequent OAG in individuals with type 2 diabetes mellitus (T2DM). Methods: We conducted a retrospective cohort study by using data from the National Health Insurance Research Database (NHIRD) of Taiwan. Participants with T2DM were divided into those who used GLP-1RA and those who did not, forming the GLP-1RA and control groups. The primary outcome was the occurrence of OAG based on diagnostic codes. Cox proportional hazard regression was employed to calculate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for OAG. Results: 91 patients in the control group developed OAG, and 40 patients in the GLP-1RA group developed OAG. After adjustment for all covariates, the GLP-1RA group exhibited a significantly lower incidence of OAG compared with the control group (aHR: 0.712, 95% CI: 0.533-0.936. P = 0.0025). In the subgroup analyses, the association between GLP-1RA use and OAG incidence was more pronounced in patients with T2DM using GLP-1RA and aged younger than 60 years (P = 0.0438). Conclusion: The prescription of GLP-1RA is associated with a lower incidence of subsequent OAG in individuals with T2DM, and this association was more significant in patients with T2DM under the age of 60 years.
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Diabetes Mellitus Tipo 2 , Glaucoma de Ângulo Aberto , Peptídeo 1 Semelhante ao Glucagon , Humanos , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Glaucoma de Ângulo Aberto/tratamento farmacológico , Glaucoma de Ângulo Aberto/epidemiologia , Peptídeo 1 Semelhante ao Glucagon/agonistas , Prescrições , Estudos RetrospectivosRESUMO
Sodium-glucose cotransporter 2 (SGLT2) inhibitors revealed the protective function on various systemic diseases. This study aimed to determine whether the usage of SGLT2 inhibitors associates with incidences of superficial keratopathy and infectious keratitis in type 2 diabetes mellitus (T2DM) patients. A retrospective cohort study with the usage of National Health Insurance Research Database of Taiwan was conducted. The T2DM patients were divided into the SGLT2 inhibitors and control groups according to the usage of SGLT2 inhibitors or not. The major outcomes were defined as the occurrence of superficial keratopathy and infectious keratitis. There were 766 and 1037 episodes of superficial keratopathy in the SGLT2 inhibitors and control groups and SGLT2 inhibitors group showed a significantly lower incidence of superficial keratopathy than the control group (aHR: 0.721, 95% CI: 0.656-0.791, P < 0.0001). Also, there were 166 and 251 infectious keratitis events in the SGLT2 inhibitors and control groups and patients in the SGLT2 inhibitors group revealed a significantly lower infectious keratitis incidence than those in the control group (aHR: 0.654, 95% CI: 0.537-0.796, P < 0.0001). In addition, the patients that received SGLT2 inhibitors demonstrated lower cumulative incidences of both superficial keratopathy and infectious keratitis compared to the non-SGLT2 inhibitors users (both P < 0.0001). In conclusion, the usage of SGLT2 inhibitors correlates to lower incidence of superficial keratopathy and infectious keratitis in T2DM individuals, which is more significant in patients with persistent SGLT2 inhibitors application.
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Doenças da Córnea , Diabetes Mellitus Tipo 2 , Ceratite , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Doenças da Córnea/complicações , Diabetes Mellitus Tipo 2/complicações , Hipoglicemiantes , Incidência , Ceratite/complicações , Estudos RetrospectivosRESUMO
The genome consists of non-B-DNA structures such as G-quadruplexes (G4) that are involved in the regulation of genome stability and transcription. Telomeric-repeat containing RNA (TERRA) is capable of folding into G-quadruplex and interacting with chromatin remodeler ATRX. Here we show that TERRA modulates ATRX occupancy on repetitive sequences and over genes, and maintains DNA G-quadruplex structures at TERRA target and non-target sites in mouse embryonic stem cells. TERRA prevents ATRX from binding to subtelomeric regions and represses H3K9me3 formation. G4 ChIP-seq reveals that G4 abundance decreases at accessible chromatin regions, particularly at transcription start sites (TSS) after TERRA depletion; such G4 reduction at TSS is associated with elevated ATRX occupancy and differentially expressed genes. Loss of ATRX alleviates the effect of gene repression caused by TERRA depletion. Immunostaining analyses demonstrate that knockdown of TERRA diminishes DNA G4 signals, whereas silencing ATRX elevates G4 formation. Our results uncover an epigenetic regulation by TERRA that sequesters ATRX and preserves DNA G4 structures.
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Quadruplex G , RNA Longo não Codificante , Animais , Camundongos , Cromatina/genética , Epigênese Genética , Telômero/genética , Telômero/metabolismo , RNA Longo não Codificante/metabolismo , DNA , Proteína Nuclear Ligada ao X/genética , Proteína Nuclear Ligada ao X/metabolismoRESUMO
BACKGROUND: Freezing of gait (FOG) is an episodic and highly disabling symptom of Parkinson's Disease (PD). Traditionally, FOG assessment relies on time-consuming visual inspection of camera footage. Therefore, previous studies have proposed portable and automated solutions to annotate FOG. However, automated FOG assessment is challenging due to gait variability caused by medication effects and varying FOG-provoking tasks. Moreover, whether automated approaches can differentiate FOG from typical everyday movements, such as volitional stops, remains to be determined. To address these questions, we evaluated an automated FOG assessment model with deep learning (DL) based on inertial measurement units (IMUs). We assessed its performance trained on all standardized FOG-provoking tasks and medication states, as well as on specific tasks and medication states. Furthermore, we examined the effect of adding stopping periods on FOG detection performance. METHODS: Twelve PD patients with self-reported FOG (mean age 69.33 ± 6.02 years) completed a FOG-provoking protocol, including timed-up-and-go and 360-degree turning-in-place tasks in On/Off dopaminergic medication states with/without volitional stopping. IMUs were attached to the pelvis and both sides of the tibia and talus. A temporal convolutional network (TCN) was used to detect FOG episodes. FOG severity was quantified by the percentage of time frozen (%TF) and the number of freezing episodes (#FOG). The agreement between the model-generated outcomes and the gold standard experts' video annotation was assessed by the intra-class correlation coefficient (ICC). RESULTS: For FOG assessment in trials without stopping, the agreement of our model was strong (ICC (%TF) = 0.92 [0.68, 0.98]; ICC(#FOG) = 0.95 [0.72, 0.99]). Models trained on a specific FOG-provoking task could not generalize to unseen tasks, while models trained on a specific medication state could generalize to unseen states. For assessment in trials with stopping, the agreement of our model was moderately strong (ICC (%TF) = 0.95 [0.73, 0.99]; ICC (#FOG) = 0.79 [0.46, 0.94]), but only when stopping was included in the training data. CONCLUSION: A TCN trained on IMU signals allows valid FOG assessment in trials with/without stops containing different medication states and FOG-provoking tasks. These results are encouraging and enable future work investigating automated FOG assessment during everyday life.
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Aprendizado Profundo , Transtornos Neurológicos da Marcha , Doença de Parkinson , Humanos , Pessoa de Meia-Idade , Idoso , Doença de Parkinson/complicações , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/diagnóstico , Transtornos Neurológicos da Marcha/diagnóstico , Transtornos Neurológicos da Marcha/etiologia , Marcha , MovimentoRESUMO
BACKGROUND: With its minimally invasive approach, laparoscopic surgery has transformed the medical landscape. As the demand for these procedures escalates, there is a pressing need for adept surgeons trained in laparoscopic techniques. However, current training often falls short of catering to medical school education. This study evaluates the impact of a custom-designed laparoscopic training workshop on medical students' surgical skills and career aspirations. METHODS: This prospective experimental study was conducted at the E-Da hospital in Kaohsiung City, Taiwan. Medical students from Taiwanese medical schools undergoing Clerk 5, Clerk 6, and Postgraduate Year 1 and 2 were invited to participate. Medical students (n = 44) underwent an endoscopic skill training workshop consisting of lectures, box training, and live tissue training. The trainees performed multiple tasks before and after training using our objective evaluation system. The primary outcome was assessed before and after training through a questionnaire assessing the influence of training on students' interest in surgery as a career. The secondary outcome measured improvement in skill acquisition, comparing the task completion time pre- and post-workshop. For the primary outcome, descriptive statistics were used to summarize the questionnaire responses, and paired t-tests were performed to determine significant changes in interest levels post-workshop. For the secondary outcome, paired t-tests were used to compare the time recorded pre- and post-training. RESULTS: Post-training, participants exhibited significant proficiency gains, with task completion times reducing notably: 97 s (p = 0.0015) for Precision Beads Placement, 88.5 s (p < 0.0001) for Beads Transfer Exercise, 95 s (p < 0.0001) for Precision Balloon Cutting, and 137.8 s (p < 0.0001) for Intracorporeal Suture. The primary outcome showcased an increased mean score from 8.15 pre-workshop to 9.3 post-workshop, indicating a bolstered interest in surgery as a career. Additionally, post-training sentiment analysis underscored a predominant inclination toward surgery among 88% of participants. CONCLUSION: The custom-designed laparoscopic workshop significantly improved technical skills and positively influenced students' career aspirations toward surgery. Such hands-on training workshops can play a crucial role in medical education, bridging the gap between theoretical knowledge and practical skills and potentially shaping the future of budding medical professionals.
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Escolha da Profissão , Competência Clínica , Laparoscopia , Estudantes de Medicina , Humanos , Laparoscopia/educação , Estudos Prospectivos , Feminino , Taiwan , Masculino , Educação de Graduação em Medicina/métodos , Adulto Jovem , AdultoRESUMO
BACKGROUND/PURPOSE: Laparoscopic sleeve gastrectomy (LSG) is an effective treatment for patients with morbid obesity, but the optimal gastric volume (GV) for resection remains unclear. Accordingly, we aimed to determine the optimal percentage of excised stomach that could engender significant weight loss and improve fatty liver. METHODS: This prospective study included 63 patients. Computed tomography (CT) scans were performed before and 1 year after LSG to evaluate the gastric lumen (GL) and GV. Specifically, the stomach was distended with effervescent powder, following water-contrast mixture (20:1) and assessed by three-dimensional reconstruction. The correlations of reduced gastric lumen/volume (RGL/RGV) with total body weight (BW) loss and liver-spleen density ratio (LSDR) changes were analyzed, and optimal RGL/RGV associated with significant BW and fatty liver changes were determined. RESULTS: We noted a positive correlation between the percentage of RGV/RGL (%RGV/%RGL) and percentage of total weight loss (%TWL; r = 0.359, p = 0.004 and r = 0.271, p = 0.032). Furthermore, a %RGL value of >78.2% and %RGV value of >75.3% were associated with more significant BW loss than did limited excision (both p < 0.01). On the other hand, LSDR values increased significantly after LSG, corresponding to the improvement of fatty liver disease at %RGL and %RGV values of >59.1% and >56.4% (both p < 0.01), respectively. CONCLUSION: %RGV and %RGL were determined to be factors affecting LSG outcomes. LSG engendered significantly more BW loss when %RGV was >75.3% and resulted in fatty liver disease improvement when %RGV was >56.4%.
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OBJECTIVE: Motivated by Health Care 4.0, this study aims to reducing the dimensionality of traditional EEG features based on manual extracted features, including statistical features in the time and frequency domains. METHODS: A total of 22 multi-scale features were extracted from the UNM and Iowa datasets using a 4th order Butterworth filter and wavelet packet transform. Based on single-channel validation, 29 channels with the highest R2 scores were selected from a pool of 59 common channels. The proposed channel selection scheme was validated on the UNM dataset and tested on the Iowa dataset to compare its generalizability against models trained without channel selection. RESULTS: The experimental results demonstrate that the proposed model achieves an optimal classification accuracy of 100%. Additionally, the generalization capability of the channel selection method is validated through out-of-sample testing based on the Iowa dataset Conclusions: Using single-channel validation, we proposed a channel selection scheme based on traditional statistical features, resulting in a selection of 29 channels. This scheme significantly reduced the dimensionality of EEG feature vectors related to Parkinson's disease by 50%. Remarkably, this approach demonstrated considerable classification performance on both the UNM and Iowa datasets. For the closed-eye state, the highest classification accuracy achieved was 100%, while for the open-eye state, the highest accuracy reached 93.75%.
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Eletroencefalografia , Doença de Parkinson , Humanos , Eletroencefalografia/métodos , Doença de Parkinson/diagnóstico , Doença de Parkinson/fisiopatologia , Algoritmos , Processamento de Sinais Assistido por Computador , Masculino , Feminino , Pessoa de Meia-Idade , Análise de OndaletasRESUMO
Parkinson's disease (PD) is the second most prevalent dementia in the world. Wearable technology has been useful in the computer-aided diagnosis and long-term monitoring of PD in recent years. The fundamental issue remains how to assess the severity of PD using wearable devices in an efficient and accurate manner. However, in the real-world free-living environment, there are two difficult issues, poor annotation and class imbalance, both of which could potentially impede the automatic assessment of PD. To address these challenges, we propose a novel framework for assessing the severity of PD patient's in a free-living environment. Specifically, we use clustering methods to learn latent categories from the same activities, while latent Dirichlet allocation (LDA) topic models are utilized to capture latent features from multiple activities. Then, to mitigate the impact of data imbalance, we augment bag-level data while retaining key instance prototypes. To comprehensively demonstrate the efficacy of our proposed framework, we collected a dataset containing wearable-sensor signals from 83 individuals in real-life free-living conditions. The experimental results show that our framework achieves an astounding 73.48% accuracy in the fine-grained (normal, mild, moderate, severe) classification of PD severity based on hand movements. Overall, this study contributes to more accurate PD self-diagnosis in the wild, allowing doctors to provide remote drug intervention guidance.
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Doença de Parkinson , Dispositivos Eletrônicos Vestíveis , Humanos , Doença de Parkinson/diagnóstico , Movimento , Índice de Gravidade de Doença , Extremidade SuperiorRESUMO
The largest Fermi surface sheet of the correlated metal Sr_{2}RuO_{4} can be driven through a Lifshitz transition between an electronlike and an open geometry by uniaxial stress applied along the [100] lattice direction. Here, we investigate the effect of this transition on the longitudinal resistivity ρ_{xx} and the Hall coefficient R_{H}. ρ_{xx}(T), when Sr_{2}RuO_{4} is tuned to this transition, is found to have a T^{2}logT form, as expected for a Fermi liquid tuned to a Lifshitz transition. R_{H} is found to become more negative as the Fermi surface transitions from an electronlike to an open geometry, opposite to general expectations from this change in topology. The magnitude of the change in R_{H} implies that scattering changes throughout the Brillouin zone, not just at the point in k space where the transition occurs. In a model of orbital-dependent scattering, the electron-electron scattering rate on sections of Fermi surface with xy orbital weight is found to decrease dramatically.
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BACKGROUND: Nonsense-mediated messenger RNA (mRNA) decay increases targeted mRNA degradation and has been implicated in the regulation of gene expression in neurons. The authors hypothesized that nonsense-mediated µ-opioid receptor mRNA decay in the spinal cord is involved in the development of neuropathic allodynia-like behavior in rats. METHODS: Adult Sprague-Dawley rats of both sexes received spinal nerve ligation to induce neuropathic allodynia-like behavior. The mRNA and protein expression contents in the dorsal horn of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by the von Frey test and the burrow test. RESULTS: On Day 7, spinal nerve ligation significantly increased phosphorylated upstream frameshift 1 (UPF1) expression in the dorsal horn (mean ± SD; 0.34 ± 0.19 in the sham ipsilateral group vs. 0.88 ± 0.15 in the nerve ligation ipsilateral group; P < 0.001; data in arbitrary units) and drove allodynia-like behaviors in rats (10.58 ± 1.72 g in the sham ipsilateral group vs. 1.19 ± 0.31 g in the nerve ligation ipsilateral group, P < 0.001). No sex-based differences were found in either Western blotting or behavior tests in rats. Eukaryotic translation initiation factor 4A3 (eIF4A3) triggered SMG1 kinase (0.06 ± 0.02 in the sham group vs. 0.20 ± 0.08 in the nerve ligation group, P = 0.005, data in arbitrary units)-mediated UPF1 phosphorylation, leading to increased nonsense-mediated mRNA decay factor SMG7 binding and µ-opioid receptor mRNA degradation (0.87 ± 0.11-fold in the sham group vs. 0.50 ± 0.11-fold in the nerve ligation group, P = 0.002) in the dorsal horn of the spinal cord after spinal nerve ligation. Pharmacologic or genetic inhibition of this signaling pathway in vivo ameliorated allodynia-like behaviors after spinal nerve ligation. CONCLUSIONS: This study suggests that phosphorylated UPF1-dependent nonsense-mediated µ-opioid receptor mRNA decay is involved in the pathogenesis of neuropathic pain.
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Hiperalgesia , Neuralgia , Masculino , Feminino , Ratos , Animais , Hiperalgesia/metabolismo , Ratos Sprague-Dawley , Degradação do RNAm Mediada por Códon sem Sentido , Medula Espinal/metabolismo , Nervos Espinhais , Neuralgia/metabolismo , Corno Dorsal da Medula Espinal , Receptores Opioides , Ligadura/efeitos adversosRESUMO
PURPOSE: Catheter-directed therapy has been increasingly used in acute pulmonary embolism (PE). Whether ultrasound-assisted thrombolysis (USAT) is superior to standard catheter-directed thrombolysis (SCDT) remains unclear. This is a systemic review and meta-analysis of comparative trials on USAT and SCDT for PE to determine whether either modality yielded better clinical efficacy and safety. MATERIALS AND METHOD: Major databases including PubMed, Embase, Cochrane Central, and Web of Science were searched through March 16, 2023. Studies that reported outcomes of SCDT and USAT for acute PE were included. Studies reported data on therapeutic efficacy (a reduction in the right ventricle [RV]/left ventricle [LV] ratio, a reduction in the systolic pulmonary artery pressure [mm Hg], change in Miller index, length of intensive care unit [ICU] and hospital stay) and safety outcomes (in-hospital mortality, overall and major bleeding events). RESULTS: A total of 9 studies with 2610 patients were included in the meta-analysis. The analysis showed significantly greater improvement in the RV/LV ratio in the SCDT group than in the USAT group (mean difference [MD]: -0.155; 95% confidence interval [CI]: -0.249 to -0.006). No statistically significant differences were found between groups comparing change in systolic pulmonary artery pressure (MD: 0.592 mm Hg; 95% CI: -2.623 to 3.807), change in Miller index (MD: -4.1%; 95% CI: -9.5 to 1.3%), hospital stay (MD: 0.372 days; 95% CI: -0.972 to 1.717), and ICU stay (MD: -0.073.038 days; 95% CI: -1.184 to 1). No significant difference was noted in safety outcomes, including in-hospital mortality (pooled odds ratio: 0.984; 95% CI: 0.597 to 1.622), and major bleeding (pooled odds ratio: 1.162; 95% CI: 0.714 to 1.894). CONCLUSIONS: In our meta-analysis of observational and randomized studies, USAT is not superior to SCDT in patients with acute PE.INSPLAY registration number: INPLASY202240082. CLINICAL IMPACT: This study compared SCDT and USAT in patients with acute pulmonary embolism. We found no additional benefit in PA pressure change, thrombus reduction, hospital stay, mortality and major bleeding rate. Additional study using consistent treatment protocol is necessary for further investigation.
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BACKGROUND: The microtubule-stabilizing drug paclitaxel (PTX) is an important chemotherapeutic agent for cancer treatment and causes peripheral neuropathy as a common side effect that substantially impacts the functional status and quality of life of patients. The mechanistic role for NIMA-related kinase 2 (NEK2) in the progression of PTX-induced neuropathic pain has not been established. METHODS: Adult male Sprague-Dawley rats intraperitoneally received PTX to induce neuropathic pain. The protein expression levels in the dorsal root ganglion (DRG) of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by von Frey tests and hot plate tests. RESULTS: PTX increased phosphorylation of the important microtubule dynamics regulator NEK2 in DRG neurons and induced profound neuropathic allodynia. PTX-activated phosphorylated NEK2 (pNEK2) increased jumonji domain-containing 3 (JMJD3) protein, a histone demethylase protein, to specifically catalyze the demethylation of the repressive histone mark H3 lysine 27 trimethylation (H3K27me3) at the Trpv1 gene, thereby enhancing transient receptor potential vanilloid subtype-1 (TRPV1) expression in DRG neurons. Moreover, the pNEK2-dependent PTX response program is regulated by enhancing p90 ribosomal S6 kinase 2 (RSK2) phosphorylation. Conversely, intrathecal injections of kaempferol (a selective RSK2 activation antagonist), NCL 00017509 (a selective NEK2 inhibitor), NEK2-targeted siRNA, GSK-J4 (a selective JMJD3 inhibitor), or capsazepine (an antagonist of TRPV1 receptor) into PTX-treated rats reversed neuropathic allodynia and restored silencing of the Trpv1 gene, suggesting the hierarchy and interaction among phosphorylated RSK2 (pRSK2), pNEK2, JMJD3, H3K27me3, and TRPV1 in the DRG neurons in PTX-induced neuropathic pain. CONCLUSIONS: pRSK2/JMJD3/H3K27me3/TRPV1 signaling in the DRG neurons plays as a key regulator for PTX therapeutic approaches.
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Antineoplásicos , Neuralgia , Humanos , Ratos , Masculino , Animais , Paclitaxel/efeitos adversos , Paclitaxel/metabolismo , Hiperalgesia/induzido quimicamente , Hiperalgesia/genética , Ratos Sprague-Dawley , Gânglios Espinais , Fosfatos/efeitos adversos , Fosfatos/metabolismo , Histonas/metabolismo , Qualidade de Vida , Canais de Cátion TRPV , Neuralgia/induzido quimicamente , Neuralgia/genética , Neuralgia/metabolismo , Antineoplásicos/efeitos adversos , Neurônios/metabolismo , Epigênese Genética , Quinases Relacionadas a NIMA/genética , Quinases Relacionadas a NIMA/metabolismoRESUMO
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have protective effects against various systemic diseases and neoplasms. This retrospective cohort study evaluated the severity of dry eye disease (DED) in patients with type 2 diabetes mellitus (T2DM) who were treated with SGLT2 inhibitors. Data were obtained from the National Health Insurance Research Database of Taiwan. Patients with T2DM who were treated with SGLT2 inhibitors were assigned to the SGLT2 group. Each patient in the SGLT2 group was matched to two individuals with T2DM who had not used SGLT2 inhibitors, constituting the control group. The primary outcomes were the development of DED and severe DED. A diagnosis of severe DED was indicated by the usage of cyclosporine. Cox proportional hazard regression was applied to yield adjusted hazard ratios (aHR) and 95% confidence intervals (CIs). In the SGLT2 group, 1864 new DED events and 147 severe DED events were recorded. Conversely, 4367 new DED events and 392 severe DED events were recorded in the control group. The incidence (aHR: 0.858, 95% CI: 0.811-0.908, p = 0.0010) and severity (aHR: 0.652, 95% CI: 0.481-0.777, p = 0.0006) of DED were significantly lower in the SGLT2 group than the control group after adjusting for multiple covariates. In subgroup analyses, the incidence and severity of DED were significantly lower in patients younger than 60 years old who were treated with SGLT2 inhibitors than in their older counterparts (p = 0.0008 and 0.0011, respectively). In conclusion, utilization of SGLT2 inhibitors in the T2DM population could reduce both the incidence and severity of DED.
Assuntos
Diabetes Mellitus Tipo 2 , Síndromes do Olho Seco , Inibidores do Transportador 2 de Sódio-Glicose , Humanos , Pessoa de Meia-Idade , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/epidemiologia , Hipoglicemiantes/uso terapêutico , Gravidade do Paciente , Estudos Retrospectivos , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêuticoRESUMO
STUDY OBJECTIVE: To evaluate whether aggressive cervical dilation is effective for creating the initial perforation between noncommunicating cavities of the complete septate uterus (CSU), which serves as the first step of hysteroscopic cervix-preserving metroplasty (CPM). DESIGN: A retrospective cohort. SETTING: A tertiary referral center. PATIENTS: Fifty-three patients with CSU were diagnosed using vaginal examinations, combined two- and three-dimensional vaginal ultrasounds, and office-based hysteroscopies. INTERVENTIONS: Patients who had received hysteroscopic CPM with the initial perforation created by aggressive cervical dilation or by the traditional method of bougie-guided incisions were compared. MEASUREMENTS AND MAIN RESULTS: Of the 53 patients with CSU, 44 patients received hysteroscopic CPM that required the creation of a perforation. Patients who received aggressive cervical dilation for creation of the perforation had nonsignificantly shorter surgical times (33.5 minutes, 95% confidence interval [CI], 28.4-38.6 vs 48.7 minutes, 95% CI, 28.2-71.3, p = .099), used significantly lower volumes of distending media (3.6 liters, 95% CI, 3.1-4.1 vs 6.8 liters, 95% CI, 4.2-9.3, p <.001), and had higher success rates (84.4%, 95% CI, 67.2-94.7 vs 50.0%, 95% CI, 21.1-78.9, p = .019). The sites of perforation all occurred on the endocervical septum and were generally fibrous and avascular. CONCLUSION: We present a novel, effective method for creating the initial perforation in hysteroscopic CPM. The success may be because of the existence of a potential weakness in the septum of the duplicated cervix, which spontaneously tears upon aggressive mechanical dilation. The method forgoes the risks associated with sharp incisions based on potentially unreliable cues and may greatly simplify the procedure.
Assuntos
Colo do Útero , Útero Septado , Gravidez , Feminino , Humanos , Colo do Útero/cirurgia , Estudos de Coortes , Estudos Retrospectivos , Dilatação/efeitos adversos , Útero/cirurgia , Histeroscopia/métodosRESUMO
Single-stranded DNA-binding proteins (SSBs) play a crucial role in DNA metabolism by binding and stabilizing single-stranded DNA (ssDNA) intermediates. Through their multifaceted roles in DNA replication, recombination, repair, replication restart, and other cellular processes, SSB emerges as a central player in maintaining genomic integrity. These attributes collectively position SSBs as essential guardians of genomic integrity, establishing interactions with an array of distinct proteins. Unlike Escherichia coli, which contains only one type of SSB, some bacteria have two paralogous SSBs, referred to as SsbA and SsbB. In this study, we identified Staphylococcus aureus SsbA (SaSsbA) as a fresh addition to the roster of the anticancer drug 5-fluorouracil (5-FU) binding proteins, thereby expanding the ambit of the 5-FU interactome to encompass this DNA replication protein. To investigate the binding mode, we solved the complexed crystal structure with 5-FU at 2.3 Å (PDB ID 7YM1). The structure of glycerol-bound SaSsbA was also determined at 1.8 Å (PDB ID 8GW5). The interaction between 5-FU and SaSsbA was found to involve R18, P21, V52, F54, Q78, R80, E94, and V96. Based on the collective results from mutational and structural analyses, it became evident that SaSsbA's mode of binding with 5-FU diverges from that of SaSsbB. This complexed structure also holds the potential to furnish valuable comprehension regarding how 5-FU might bind to and impede analogous proteins in humans, particularly within cancer-related signaling pathways. Leveraging the information furnished by the glycerol and 5-FU binding sites, the complexed structures of SaSsbA bring to the forefront the potential viability of several interactive residues as potential targets for therapeutic interventions aimed at curtailing SaSsbA activity. Acknowledging the capacity of microbiota to influence the host's response to 5-FU, there emerges a pressing need for further research to revisit the roles that bacterial and human SSBs play in the realm of anticancer therapy.